Shiro Shirakura

Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer's disease.

Angiotensin-converting enzyme (ACE) inhibitors have clinically been widely used as anti-hypertensive agents. In the present study, we compared the effects of a centrally active ACE inhibitor, perindopril, with those of non-centrally active ACE inhibitors, imidapril and enalapril, on cognitive performance in amyloid beta(Abeta) (25-35)-injected mice, a rodent model of Alzheimers disease. We also determined the brain ACE activity in order to elucidate the relationship between the cognitive function and ACE inhibition in the brain. Abeta(25-35)-injected mice showed a cognitive impairment in spontaneous alteration and object recognition tests, the indices of immediate working memory and relatively long-term recognition memory, respectively. As indicated by these tests, the oral administration of perindopril (0.1, 0.3 or 1mg/kg/day) significantly reversed the cognitive impairment in these mice, whereas neither imidapril (0.3, 1 or 3mg/kg/day) nor enalapril (1, 3 or 10mg/kg/day) had any effect on cognitive performance. Perindopril (1mg/kg/day), imidapril (3mg/kg/day), or enalapril (10mg/kg/day) all inhibited the plasma ACE activities by more than 90%. Using the same dosing regimen, only perindopril inhibited the brain ACE activities by more than 50%, whereas imidapril and enalapril showed much less potent effects. These results suggest that perindopril ameliorated the cognitive impairment in the Alzheimers disease model mice through the inhibition of brain ACE activity, but not peripheral ACE activity. Based on our observations, we concluded that a centrally active ACE inhibitor, perindopril, may therefore have a beneficial effect on Alzheimers disease as well as hypertension.

Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R.

Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca2+ channels. More recently, it has been demonstrated that benidipine inhibits T-type Ca2+ channels in addition to L-type Ca2+ channels. Therefore, effect of calcium channel blockers, including benidipine, on aldosterone production and T-type Ca2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that benidipine concentration-dependently inhibited T-type Ca2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-beta-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca2+ influx inhibitory activities of benidipine for aldosterone production. T-type Ca2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca2+ channels.

Discovery of novel 5,5-diarylpentadienamides as orally available transient receptor potential vanilloid 1 (TRPV1) antagonists.

We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood-brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury.

Foam cells generated by a combination of hyperglycemia and hyperlipemia in rats

Diabetes is a major risk factor for atherosclerosis, as well as hyperlipemia. Investigators have suggested that denatured lipoprotein in hyperglycemia transforms macrophages into foam cells, which correlates with the development or progression of atherosclerosis. In the present study, we  examined  the  generation  of  foam  cells  in  rats  caused by a combination of hyperglycemia and hyperlipemia. Streptozotocin‐induced diabetic male Wister rats were fed a high cholesterol diet (HCD) containing 1% cholesterol and 0.5% cholic acid to maintain a hyperglycemic and hyperlipemic state. Animals fed the HCD for 8 weeks or longer showed a high incidence of foam cell accumulation in the renal glomerulus, intima of aortic arch, splenic red pulp and marginal zone, liver sinusoid and intestinal lamina propria. The foam cells exhibited positive staining for antimonocyte/macrophage antibody and lipids in all these tissues. Anti‐rat apolipoprotein B (apo B) antibody revealed that positive staining existed only in the cytoplasm of glomerular foam cells. These results suggest that the origin of these foam cells can be attributed to lipid‐laden macrophages. The generation of foam cells in the hyperglycemia‐hyperlipidemia supervening rat model presented in the present study might be a useful tool for investigations of the pathogenesis of foam cells.

N-(1-phenyl-2-benzimidazolyl)-N′-phenylurea derivatives as potent in hibitors of acylcoa:cholesterol acyltransferase (ACAT)

Abstract A novel series of N-(1-phenyl-2-benzimidazolyl)-N′-phenylurea derivatives were prepared as ACAT inhibitors. These compounds showed potent ACAT inhibitory activity in vitro (liver microsomes from cholesterol-fed rabbits) and hypocholesterolemic activity in vivo (cholesterol-fed golden hamsters).